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標題: | 環境溫度透過神經胜肽受體調控線蟲壽命之神經機轉 The Neuropeptide Receptor FRPR-8 Regulates Lifespan in a C. elegans Thermosensory Circuit |
作者: | Yi-Han Lee 李意涵 |
指導教授: | 潘俊良(Chun-Liang Pan) |
關鍵字: | 線蟲,神經胜?受體,環境溫度,老化, C. elegans,neuropeptide receptors,environmental temperature,aging, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 環境溫度對於影響壽命是重要因素之一,在過去研究中已知線蟲C. elegans中有特定的基因與神經元負責維持高溫時的壽命,而在我們上篇研究中,發現溫度感覺神經元AFD所分泌神經胜肽FLP-6是恆定高溫時壽命的訊息。在本篇研究中,我們藉由表現線蟲的所有G蛋白偶聯受體在中國倉鼠卵巢細胞,並將之與各種合成神經胜肽作用,藉此篩選出能與G蛋白偶聯受體結合的神經胜肽。我們找到了神經胜肽受體FRPR-8能與神經胜肽FLP-6作用,並且發現到失去frpr-8所造成的在高溫時壽命縮短的現象類似於flp-6,而同時失去frpr-8與flp-6並不會更加縮短線蟲在高溫時的壽命,再加上喪失frpr-8會完全阻斷過量表現flp-6所造成的壽命延長情形,證實frpr-8與flp-6作用在同一條路徑上,且frpr-8是flp-6的受體。frpr-8表現在腸道細胞與感覺神經AWC、ASK,與中間神經元SIA、PVR,目前我們還無法偵測到frpr-8是否表現在中間神經元AIY,但在frpr-8缺失的動物中,藉由單獨表現frpr-8在中間神經元AIY能夠完全恢復到正常壽命,而單獨在中間神經元AIY中剔除掉frpr-8,其壽命則縮短至相類似於frpr-8缺失的動物,證明frpr-8藉由作用於中間神經元AIY中來調控動物在高溫時的壽命。進一步,我們證明神經胜肽受體FRPR-8也是類似於神經胜肽FLP-6會透過daf-16/FoxO調控壽命。本篇研究發現了一條從溫度感覺神經元所分泌的神經胜肽與其在中間神經元上受體所構成的神經迴路,來幫助線蟲維持在高溫時的壽命。 Longevity is regulated by sensory experience, but the neural basis is incompletely understood. Previous studies have identified genes, neurons, and signals that maintain C. elegans lifespan at warmer temperature. Our previous work finds that the AFD thermosensory neuron secretes FLP-6, an FMRFamide neuropeptide essential for lifespan at warm temperature. Through screening C. elegans G protein-coupled receptors against a library of synthetic neuropeptides, we find that FRPR-8 is a likely candidate FLP-6 receptor. Lifespan reduction at warm temperature is observed in three frpr-8 alleles, phenocopying the flp-6 mutant. The flp-6; frpr-8 double mutant showed a lifespan similar to that of the frpr-8 mutant, suggesting that flp-6 and frpr-8 function in the same genetic pathway. Furthermore, frpr-8 mutations blocked the lifespan extension conferred by flp-6 overexpression, suggesting that frpr-8 acts downstream of flp-6. frpr-8 is expressed in the intestine as well as a few neurons, including the AWC and ASK chemosensory neurons, and the SIA and PVR interneurons. Although we failed to detect frpr-8 expression in AIY interneuron, expression of frpr-8 in the AIY interneuron, but not in the intestine or the ASK sensory neuron, fully rescued the short lifespan of the frpr-8 mutant. Consistent with our previous finding that flp-6 regulates longevity through daf-16/FoxO, our double mutant analysis suggests that frpr-8 and daf-16 act in a common longevity pathway. Progress in this project will improve our understanding of the circuit basis for longevity response to warm temperature in C. elegans. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72604 |
DOI: | 10.6342/NTU201902310 |
全文授權: | 有償授權 |
顯示於系所單位: | 分子醫學研究所 |
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